Division of Immunogenetics

Prof. Dr. Peter Krammer

The Division has made groundbreaking contributions to the field of programmed cell death (apoptosis). The group established that the CD95 receptor does not only act as a death receptor that induces apoptosis, but it also triggers the NF-kB pathway involved in tumor proliferation, invasion and metastasis. Together with APOGENIX, a company founded with DKFZ, the group has developed the biological, APG101, a soluble fusion protein consisting of two extracellular domains of the CD95 receptor and an antibody Fc fragment (CD95-Fc). APG101 has therapeutic effects in many diseases, e.g. in cancer.
Two TCM anti-cancer compounds, Wogonin and Rocaglamide, could be shown to preferentially induce apoptosis in tumor cells. Cyclin-dependent kinase 9 (CDK9) was identified as the direct molecular target of Wogonin, and Prohibitin 1 and 2 were identified as targets of Rocaglamide. Annexins were shown to be involved in induction of peripheral tolerance against antigens from apoptotic cells. They are transferred early upon induction of cell death to the surface of apoptotic cells. By inhibition of NF-?B signaling, annexins suppress dendritic cell (DC) maturation.
A redox-regulating molecule, AF-1, was identified as being associated with aging of human cells. Knockdown of AF-1 can also substantially extend stress resistance and life span in Drosophila. AF-1 seems to be involved in a general aging mechanism.

FUTURE OUTLOOK
Future work will be directed at trying to block the CD95 death pathway. CD95 mediated non-death pathways will be addressed by re-sensitization towards apoptosis by drugs, and blocking of CD95 receptor signaling by drugs and/or soluble CD95 receptors. Further trials with the soluble CD95 receptor APG101 are planned. The molecular interactions of Wogonin and Rocaglamide to their targets will be elucidated, and will serve as a platform for further drug screening. The influence on cell death of tumor cells from novel NF-?B regulating phosphatases will be characterized in order to find ways to manipulate them to treat patients. Annexins on the surface of apoptotic tumor cells suppress the anti-tumor immune response. Therefore, manipulation of the annexin system promises benefits for tumor therapy. The group will focus on the identification of the annexin receptor and the molecular mechanism by which annexin treatment inhibits pro-inflammatory signaling. Future directions of the group’s work will involve the investigation of the role of AF-1 as a putative master switch in aging. We will focus on AF-1’s molecular mechanism, its druggability, and its role in age-related diseases.

Contact

Prof. Dr. Peter Krammer
Immunogenetics (D030)
Deutsches Krebsforschungszentrum
Im Neuenheimer Feld 280
69120 Heidelberg
Tel: +49 6221 42 3718

Selected Publications

  • Brechmann M. et al. (2012). A PP4 holoenzyme balances physiological and oncogenic nuclear factor-kappa B signaling in T lymphocytes. Immunity, 37(4), 697–708.
  • Kaminski M.M. et al. (2012). T cell activation is driven by an ADP-dependent glucokinase linking enhanced glycolysis with mitochondrial reactive oxygen species generation. Cell Rep, 2(5), 1300–1315.
  • Schleich K. et al. (2012). Stoichiometry of the CD95 death-inducing signaling complex: experimental and modeling evidence for a death effector domain chain model. Mol Cell, 47(2), 306–319.
  • Kiessling M.K. et al. (2011). High-throughput mutation profiling of CTCL samples reveals KRAS and NRAS mutations sensitizing tumors toward inhibition of the RAS/RAF/MEK signaling cascade. Blood, 117(8), 2433–2440.
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